Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients

Abstract

With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m(2). Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥ 1.0 mg/liter.

Fig. 1.

Steady-state plasma concentration-time profiles of the prodrug CMS (A) or formed colistin (B) in 105 critically ill patients (89 not on renal replacement, 12 on intermittent HD, and 4 on CRRT). The physician-selected daily doses of colistin base activity (CBA) ranged from 75 to 410 mg/day; the dosage intervals ranged from 8 to 24 h, and hence the interdosing blood sampling interval spanned the same range.

Fig. 2.

Relationship of physician-selected daily dose of colistin base activity (CBA) (A) and the resultant average steady-state plasma colistin concentration (B) with creatinine clearance in 105 critically ill patients.

Fig. 3.

Representative individual population PK model fits of CMS (A, C, and E) or formed colistin (B, D, and F) in critically ill patients. Panels A and B are representative of a subject not on renal replacement, C and D are representative of a subject on HD, and E and F are representative of a subject on CRRT.

Fig. 4.

Relationship between the “ideal” maintenance dose of CMS (expressed as mg per day of colistin base activity [CBA] per each 1.0 mg/liter of colistin C_ss,avg target) and creatinine clearance in 101 critically ill patients (89 not on renal replacement and 12 on HD).

Fig. 5.

Pharmacodynamic activity predicted by applying the AUC_0-24 values (from the algorithm-predicted maintenance doses targeting a colistin C_ss,avg of 2.5 mg/liter) for each of the 105 critically ill patients together with the PD parameters from 3 isolates of A. baumannii in a murine thigh infection model (unpublished PD parameter estimates referenced to total plasma colistin concentration from reference 13). The predicted logs of effect are relative to the respective baseline inocula and are plotted as a function of creatinine clearance in the critically ill patients. The symbols represent the following strains: •, 248-01-C.248 (MIC = 1.0 mg/liter); ▴, ATCC 19606 (MIC = 1.0 mg/liter); and □, N-16870.213 (MIC = 0.5 mg/liter).